Synaptic plasticity is a fundamental property of neurons that underlie mechanisms of memory, learning, and cognition. Plasticity depends upon the complex interactions of ion channels and synaptic receptors, including the excitatory glutamate N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Animal models of pharmacological or genetic disruption of these receptors result in severe alterations of memory, learning, behavior, and seizures. Therefore it is expected that immune responses against extracellular domains of these receptors would result in similar symptoms. Indeed, two recently identified disorders associated with antibodies to extracellular epitopes of the NR1 subunit of the NMDAR and the G1uR1/2 subunits of the AMPAR result in encephalitides that manifest with prominent psychiatric, behavioral, and memory problems, often accompanied by seizures. In these two synaptic autoimmunities each antibody causes a dramatic and specific decrease of the levels of the target receptor in cultured neurons, suggesting they are pathogenic. Additionally, the neurological syndromes often respond to treatment, and in some patients the immune response occurs as a paraneoplastic manifestation of a tumor that expresses the target receptor, resembling in many aspects the autoimmune disorders of the neuromuscular synapse (e.g., Lambert-Eaton syndrome and myasthenia gravis). These findings along with a remarkable antibody-syndrome specificity and high frequency of some disorders (e.g., anti-NMDAR encephalitis) have drawn attention to other syndromes in which memory and behavior are impaired and seizures occur frequently. In some of these syndromes an immune mediated pathogenesis is suggested by the clinical response to empiric immunotherapy, the CSF an MRI findings suggesting limbic encephalitis, or the detection of antibodies to yet unknown extracellular neuronal antigens.
A better understanding of the function of various antigens may help improve the treatment strategies. For the clinician who currently confronts these patients, however, the best chance to affect the neurologic outcome depends on: (1) the prompt diagnosis of the disorder, (2) the early discovery and treatment of the tumor, and (3) the use of immunotherapy. Accordingly, a need exists for improved methods of diagnosing and treating autoimmune encephalitis or epileptic seizures.